We have generated conditional glucocorticoid receptor (GR) knockout mice, which have crossed to lck-CRE animals to produce mice that lack GR expression in thymocytes and T cells. These mice have a modest reduction (about 25%) in the number of double positive (DP) and single positive (SP) thymocytes. Introduction of a transgenic T cell receptor (TCR) that has borderline affinity for self (meaning that both positive and negative selection occur) results in a much smaller thymus (60-70% reduction), indicating that the thymocytes are undergoing increased negative selection in the absence of GR signaling. If the TCR repertoire, the range of receptors expressed after selection, is indeed affected by glucocorticoids, there should be changes in the specificity of immune responses. We have found that mature T cells from the conditional GR-null mice proliferate normally to mitogens or to TCR cross-linking, but poorly to alloantigens. Moreover, immunization with peptide antigens results in a poor T cell recall response. Using various TCR transgenic models of thymocyte selection, we have shown that antigen-specific selection is altered by lack of thymocyte GR, and that the peripheral T cell repertoire is skewed towards low avidity receptors. These results strongly support the hypothesis that exposure to glucocorticoids in the thymus is a critical event in shaping the T cell repertoire, and thus the ability to respond to foreign pathgenes. Because glucocorticoids are also immunosuppressive, we have examined the immune response to several infectious models. In one such model, T. gondii, we found that mice lacking GR expression in T cells undergo a cytokine storm and die within days of infection (in contrast, wild type animals mount a functional immune response and survive). These data suggest that the response of peripheral T cells to endogenous glucocorticoids is important in controlling the limits of an immune response to prevent harmful secondary effects.